The regulatory mechanism of CCR7 gene expression and its involvement in the metastasis and progression of gastric cancer

Abstract

Gastric cancer is the second leading cause of cancer mortality, but the molecular mechanisms underlying its progression and metastasis remain unclear. CCR7 and Dicer 1 protein expression in 80 gastric adenocarcinomas and 40 peritumoral tissues were measured by immunohistochemical staining. The expression of let-7a miRNA in serum, tumor tissues, and peritumoral tissues was measured by real-time PCR. The role of let-7a in CCR7 protein expression, migration, and invasion of gastric cancer cells was tested in vitro. Dicer 1 protein expression was found to be significantly reduced, whereas CCR7 protein expression was significantly increased in gastric adenocarcinomas compared to peritumoral tissues. The let-7a miRNA levels in the serum and tumor tissues of gastric adenocarcinoma patients were significantly lower than in the serum of healthy controls and peritumoral tissues, respectively. Dicer 1 protein positively correlated with let-7a miRNA level, but negatively correlated with CCR7 protein level in gastric adenocarcinoma. Negative Dicer 1 protein and let-7a miRNA expression and positive CCR7 protein expression significantly correlated with lymph node metastasis, depth of invasion, high clinical TNM stage, and larger tumor size. Let-7a transfection significantly inhibited CCR7 protein expression, migration, and invasion of MNK-45 cells in vitro. High expression of CCR7 protein and low expression of Dicer 1 protein and let-7a miRNA are significantly associated with the metastasis and progression of gastric cancer. High CCR7 protein expression may be caused by the loss of Dicer 1 protein expression and reduced let-7a miRNA level in gastric cancer. The serum let-7a level might be a marker for the diagnosis of gastric cancer.

C‑C motif chemokine receptors in gastric cancer (Review)

“…Numerous studies have shown that CCR7 is differentially expressed in tumor cells in gastric cancer at the mRNA and protein levels, as well as in the cell membrane in vitro and in vivo (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). In addition, CCR7 was detected in tumor-infiltrating lymphocytes and dendritic cells in gastric cancer, as well as in mononuclear cells in Helicobacter pylori gastritis (35,38).…”

“…In addition, H. pylori upregulated CCR7 in CCR7-expressing gastric cancer cell lines, whereas no difference in CCR7 upregulation was identified between the cag + and cag -H. pylori strains (35,39,40). Wang et al (32) demonstrated that CCR7 protein expression was significantly higher in gastric cancer compared with peritumoral tissues, and that high levels of CCR7 expression could be induced by loss of Dicer-1 and decreased levels of let-7a microRNA (miRNA) in gastric cancer. In that study, transfection of let-7a miRNA into gastric cancer cells markedly inhibited the expression of functional CCR7, suggesting that miRNA is involved in the regulation of CCR7 expression (32).…”

“…Wang et al (32) demonstrated that CCR7 protein expression was significantly higher in gastric cancer compared with peritumoral tissues, and that high levels of CCR7 expression could be induced by loss of Dicer-1 and decreased levels of let-7a microRNA (miRNA) in gastric cancer. In that study, transfection of let-7a miRNA into gastric cancer cells markedly inhibited the expression of functional CCR7, suggesting that miRNA is involved in the regulation of CCR7 expression (32). The expression of CCR7 in gastric cancer was associated with aggressive tumor biology, including the processes of tumor invasion, lymph node metastasis, lymphatic invasion, venous invasion and an advanced stage of cancer (27)(28)(29)31,33), and this may be an important prognostic marker for survival in patients with gastric cancer (28,29,31), although contradictory data have also been reported (30).…”

Expression of chemokine receptor CCR7 is a negative prognostic factor for patients with gastric cancer: a meta-analysis

“…After excluding irrelevant articles by reviewing the titles and abstracts of those studies, two investigators (P. Du and Y. Liu) reviewed the full text version of the remaining 30 articles independently in accordance with the inclusion and exclusion criteria. Finally, 15 articles [7][8][9][10][13][14][15][16][17][18][19][20][21][22][23] comprising data on 1697 participants met the requirement of the analysis. The detailed search steps are described in Fig.…”

CCR7 Regulates Cell Migration and Invasion through JAK2/STAT3 in Metastatic Squamous Cell Carcinoma of the Head and Neck

“…The CC chemokine CCL19 and its receptor CCR7, which regulate chemotaxis and the transendothelial migration of leukocytes during immune and inflammatory reactions, were recently observed to play an important role in the metastasis of various types of cancer [2–5]. We have also reported that CCR7 regulates cell migration and adhesion in metastatic squamous cell carcinoma of the head and neck by activating integrin, PI3K/cdc42, pyk2, and Src [6–15].…”